No Established Iatrogenic Cause of Autism Except Prenatal Valproic Acid Exposure
There is no established iatrogenic cause of autism spectrum disorder (ASD) with the critical exception of maternal valproic acid use during pregnancy, which increases the risk of ASD in offspring by approximately 2.9-fold. 1
Valproic Acid: The Only Documented Iatrogenic Cause
Prenatal exposure to valproic acid (valproate) is the only medically-induced cause of ASD with robust evidence:
Maternal valproate use during pregnancy increases the absolute risk of autism spectrum disorders to 4.4% in exposed children compared to 1.5% in unexposed children (95% CI: 1.7 to 4.9 for relative risk). 1
This represents a nearly 3-fold increased risk, though the FDA label notes that because the supporting study was observational, conclusions regarding definitive causation cannot be considered absolute. 1
Valproate exposure during pregnancy also causes decreased IQ scores, neural tube defects (1-2% risk of spina bifida), and other congenital malformations, with risks present throughout pregnancy but greatest in the first trimester. 1
The FDA explicitly states that valproate should not be administered to women of childbearing potential unless essential to management of their medical condition, and should not be used to treat women with epilepsy who are pregnant or plan to become pregnant unless other treatments have failed. 1
Germline Epigenetic Disruption: Theoretical but Unproven
Some research suggests that disruption of parental germline epigenome by exogenous toxicants during gamete development (including anesthetic gases, tobacco components, synthetic steroids, and valproic acid) could theoretically contribute to ASD, but this remains speculative. 2
This mechanism differs from direct fetal exposure and could potentially explain some unexplained phenomena like missing heritability and sex ratio skewing, but lacks definitive evidence. 2
What Is NOT an Iatrogenic Cause
Immunizations, particularly the measles-mumps-rubella (MMR) vaccine, have been definitively ruled out as causes of autism:
Epidemiologic studies fail to confirm that immunizations with MMR vaccine are responsible for increases in autism prevalence. 3
The dramatic increase in reported ASD prevalence (556% between 1991-1997) is attributable to heightened awareness, broader diagnostic criteria, improved public and professional awareness, and higher acceptance of the diagnosis—not to environmental or iatrogenic influences. 4
The Predominantly Genetic Nature of ASD
Understanding that ASD is overwhelmingly genetic helps contextualize the limited role of iatrogenic factors:
Heritability is estimated at 70-90%, with 60-92% concordance in monozygotic twins versus 0-10% in dizygotic twins. 5, 3
Only approximately 20% of ASD cases have an identified genetic etiology through current testing (chromosomal abnormalities, copy number variations, single-gene mutations), leaving 80% as "idiopathic" but still presumed to be genetic. 4
Tuberous sclerosis complex and fragile X syndrome together account for less than 10% of cases. 5, 6
Sibling recurrence risk is 2-19%, substantially higher than the general population prevalence of 2.2-2.3 per 1,000. 5
Other Environmental Factors: Not Iatrogenic
While some environmental exposures have been studied in relation to ASD risk, these are not iatrogenic (medically-induced):
Advanced maternal or paternal age and extremely premature birth (less than 26 weeks gestational age) are identified risk factors but are not treatment-related. 5, 7
Research into air pollution, pesticides, plastics, prenatal vitamins, and maternal metabolic conditions during pregnancy is ongoing but does not establish iatrogenic causation. 8
Viral infections, prenatal infections (rubella, cytomegalovirus), perinatal insults, and toxic exposures account for few cases and are not treatment-induced. 3, 9
Clinical Implications
For prescribing clinicians:
Counsel all women of childbearing potential about the substantial ASD risk (and other neurodevelopmental risks) associated with valproate exposure during pregnancy. 1
Consider alternative anticonvulsants for women with epilepsy who are pregnant or planning pregnancy unless valproate is the only effective option. 1
Folic acid supplementation should be routinely recommended for patients using valproate, though it is unknown whether this reduces ASD risk specifically. 1
For families seeking answers:
Reassure families that standard medical care, including vaccinations, does not cause autism. 3
The increase in ASD diagnosis reflects better recognition, not a true epidemic or iatrogenic cause. 4, 10
Genetic evaluation is warranted for all children with ASD, as it can identify specific etiologies in 30-40% of cases and provide recurrence risk counseling. 10